Synthesis of aspartic acid



Patented Sept. 26, 1950 SYNTHESIS ASPA R' IIC ACID Donald T. Warner andOwen A. Moe, Minneapolis, Minn., assignors to General Mills, Inc., acorporation of Delaware N Drawing. ApplicationDecember 6, 1946,

Serial No. 714,647

4 Claims. (01. 260-482) The present invention relates to the synthesisof aspartic acid from novel aldehydo compounds.

These aldehydo compounds may be represented by the following structuralformula:

in which R may be hydrogen, carboxyl, carboxylic acid ester, carbonamide(CONH2, -CONHR,' etc.), or nitrile; R may be carboxyl, carboxylic acidester, carb'onamide, or nitrile; R, is a substituted amino group inwhich at least one of the hydrogens has been replaced with a group whichis capable of being removed by hydrolysis, reduction, or the like.

The esterifying group of the carboxylic acid ester in the above formulamay vary widely and may include alkyl, aryl, aralkyl, alkyaryl, andother groups such as methyl, ethyl, propyl, phenyl, benzyl, toluyl, etc.Of these, the low alkyl groups are preferred. Similar variations arepossible in the carbonamide groups. R may include such groups asphthalimido; N acyl, such as NOCCHs, NOCCsHs, etc.; N sulfonyl, forexample, NSOcCsI-Is; N carlgbenzoxy, for example, NCQOCHzCsI-Ia; and thelike. It-will be apparent that R may be mono-substituted or may bedi-substituted by any group or combination of groups of the above type.

The preparation of aspartic acid from compounds of this type involvesthe oxidation of the aldehyde group to the acid and then the hydrolysisof the various groups (ester. nitrile, carbonamide, substituted amino,etc.) to the corresponding free acid and amino groups. V

The aldehydes employed in the present process may be prepared inaccordance with the disclosure of our copending application, Serial No.714; 643, filed of even date herewith, entitled. Beta-Acetamido-Beta,Beta-Dicarbalkoxy Propionaldehydes and Process. Accordingto the application, these aldehydes may be prepared, for example, by thereaction of acetamido malonic ester or acetamido cyano acetic ester withan allylhalide to produce the corresponding allyl derivative. The doublebond in this allyl derivative may be ozonized to the ozonide, which maythen be converted to the above described aldehyde.

The oxidation of the aldehyde to the acid is comparatively simple tocarry out since the aldehydo compound displays excellentwatersolubility. The oxidation may be carried out by 2 means of any suitablemild oxidation agent, such as potassium permanganate, hydrogen peroxide,sodium chlorite, bromine water, chromic acid, and the like. Theresulting substituted propionic acid may be isolated either as thecrystalline intermediate or may be hydrolyzed directly to aspartic acid.In the hydrolysis, there are two possible routes, one involving alkalinehydrolysis,-

and the other involving acid hydrolysis. The acid hydrolysis yields'theaspartic acid directly, sinceit affects hydrolysis anddecarboxylationsimultaneously. If the alkaline hydrolysis is employed,the decarboxylation may be performed in a sep-. arate step.

The aspartic acid may be obtained in a suitable manher. For example, itmay be isolated as a copper salt. This may be obtained by the additionof copper acetate to a slightly acidic hydrolysis mixture. The coppersalt may then be crystallized and isolated, after which it may beacidified, for example by means of hydrogen sulfide which liberates theaspartic acid and at the same time precipitates the copper. The asparticacid may then be crystallized from the filtered solution.

The following example will serve to illustrate the inventon:

EXAMPLE 3.3 parts .of the aldehyde compound were dissolved in 20 partsof water with slight warming. The resulting solution was cooled and afew drops of 10% sodium hydroxide were added. A saturated aqueoussolution of potassium permanganate was added dropwise. The oxidation wasvery rapid and the solution became warm. The resulting reaction mixturewas cooled in a cold water bath as the addition of the potassiumpermanganate solution was continued. When the reaction was complete, theprecipitated manganese dioxide was removed by filtration. The clearfiltrate was acidified with dilute hydrochloric acid and the pH at thispoint was approximately 3. The very slight excess of potassiumpermanganate was removed by the addition of a dilute sodium bisulfitesolution. The resulting water-clear solution Was evaporated in vacuo toa total volume of approximately 5 ml. An inorganic precipitate was notedat this point and it was removed by filtration. The clear filtrate wasextracted with chloroform. I The chloroform extract was dried overcalcium chloride and con- The aqueous solution remaining after thechloroform extractions still contained'consider able quantities of crudebeta acetamido-beta, beta-dicarbethoxy propionic acid. It was evaporatedto dryness and a residualoilyresulted which 1 partially solidified onstanding. This residual oil was used in the subsequent hydrolysis whichwill be described in part B.

B. Hydrolysis of beta-acetamz'do-beto, betadicarbethoxy propionic acidThe abovedescribed' resi'dualoil whichjpartially solidified on standingW'a's miXod with 7. parts of concentrated hydrochloric acid. Theresulting reaction mixture wasrefiuxed' for a period of four hours. Atthi'spoint the solution possessed a light brown color. After the refluxperiod was complete, the'reactioh' mixture was diluted with a smallamount of water and evapo rated to drynessinvacuoz' Th'e'resi'duappeared as a" pasty solid; 2.5par'ts of water was'added to 'theresidue" and the" resulting solution was cooled overnight. A smallamount of the crystalline product had'depos ite'd and this was removedby filtration and proved tobe" inorganic. The lightbrow'n filtrate was;just neutralized with dilutesodiumhydroxide, then dilute "hydrochloricaoid was 'added'until the solution wasacidic to meth'ylred. C. Isolationof copper aspdrtate and aspartic 'acid The above described solutionwhich had been made-just acidicto methyl red was treated with a. hotaqueous solution of copper acetate monohydr'atef' After standing forapproximately 90 minutes, the copper salt started to crystallize as alight blue crystalline-product. This reaction mixture was permitted tostand in the refrigerator overnight; The copiousfquantitybf the coppersalt wascollected by filtrationandthecopper aspartate was air-dried.After dr'ying, the copper salt was suspended in dilute (approximatelyone normal) acetic acid. A streamof hydrogen sulfide was introduced intothe reaction mixture and the copper precipitated," a copper sulfide. The"precipitated copper sulfide'was removed by filtration and' theresulting clear filtrate was evaporated slowly in vacuo. The dl-asparticacid soon crystallized as a white crystalline product. When the totalvolume of thefiltrate was ap proximately 3 ml., it was warmed on'thesteam ture-with an alkaline permanganate to convert Clo bath untilcomplete solution was obtained. 10 parts of absolute ethyl alcohol wereadded to the clear solution, and immediately the precipitation of aWhite crystalline product Was noted. The crystalline dl-aspartic acidwas collected by filtration and washed with dilute alcohol. Afterdrying'thedl-aspartic acid melted at 300 C. with decomposition.

While various modifications of the above invention have been described,it is to be understood that the same is not limited thereto, but may bevaried within the scope of the following claims. 7 r

We claim as our invention:

1. Beta ace'tamido beta, beta dicarbethoxy propionic acid;-

2; A compound having the following formula:

COOalk oH3ooNH o oooa1k in which alk is a lower alkyl group;

3. Process of prep rin aspartic acid from a compound having thefollowing formula:

COoalk onzooNa-oqlooalk i i no" I inwhich alk is a lower alkyl group; oa-1 prises oxidizing-the, aldehyde at a low temperathe aldehyde group tothe acid, then-subjectingthe acid to hydrolysis in the presence ofconcentrated hydrochloric acid atreflux temperatures to hydrolyze anddecarboxylate said compound to aspartic acid.

4. Process of preparingaspartic acid from beta acetamido-beta,- betadicarbethoxy propionalde hyde which comprises oxidizing the aldehyde "atalow temperature with an alkaline permanganate to convert the aldehydegroup to the acid, then subjecting the acid to hydrolysis in thepresence of concentrated hydrochloric acid at reflux temperatures tohydrolyze and decarboxylate said compound to aspart ic acid;

DONALD T. WARNER: OWEN A. MOE.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED" STATES PATENTS" Name Date Amend Apr. 13, 1943 OTHER; REFERENCESNumber

1. BETA - ACETAMIDO - BETA, BETA - DICARBETHOXY PROPIONIC ACID.